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  • br Human leukocyte antigen The human leukocyte antigen

    2018-10-25


    Human leukocyte antigen The human leukocyte antigen (HLA) is the most gene-dense region of the genome, encoding >120 functional genes in humans distributed over a 3.6-Mbp region. Many of these genes function in the immune system. This region has been associated with almost all diseases involving autoimmunity, inflammation, and host defense against infections. To date, the main GV GWASs in Caucasian and Chinese populations have identified the HLA region as the strongest determinator of genetic risk. The HLA can be subdivided into three classes (I, II, and III) with a strong linkage disequilibrium (LD) spanning the region. In Caucasians, two major MHC association peaks were found. One association [including 3 single nucleotide polymorphisms (SNPs): rs12206499, rs3823355, and rs6904029] was in the class I gene region, between HLA-A (encoding the MHC class I, HLA-A molecule) and HCG9 (encoding the HLA complex group 9). The second association (including 2 SNPs: rs532098 and rs3806156) was in the class II gene region, between HLA-DRB1 (the MHC class II, DR beta 1 gene) and HLA-DQA1 (the MHC class II, DQ alpha 1 gene). There were a strong LD between the risk allele (G) at rs12206499 and HLA-A*02, and a moderate LD between the risk allele (T) at rs532098 and HLADRB1*04, which were consistent with previous reports of an association between GV and both the HLA-A*02 allele and the HLA-DRB1*04 allele. In addition, a quantitative trait locus was identified for vitiligo age of onset in the MHC class II region, located near c6orf10-BTNL2 (rs7758128), which highlights the differing roles played by genes involved in vitiligo susceptibility versus vitiligo phenotype. For the Chinese study, there were two major independent association signals within the MHC region. The most significant SNP (rs11966200) is located in the HLA class III region. Another independent statistically significant association (rs9468925) is located at the HLA-C–HLA-B region. Two haplotypes (AGAAGGCGAAC and CAGGAAAAGGG) on rs9468925 and rs11966200 as well as an additional nine top SNPs surrounding them within the MHC region were highly associated with GV. By imputing the HLA class I bupropion hydrochloride and test for association, three alleles (HLA-A*3001, HLA-B*1302, and HLA-C*0602) within the MHC region reveals strong associations, which is consistent with the previous findings of HLA association in the Chinese population. Overall, all of these studies highlight the involvement of HLA genes to the pathogenesis of GV.
    Melanin-related genes
    Immune-related genes
    Other related genes
    Conclusion
    Acknowledgments We thank Xuejun Zhang for comments and suggestions concerning this manuscript. The project was financially supported by a grant from the Natural Science Foundation of China (Grant No. 81171519) and Shanghai Municipal Health Bureau (Grant No. XBR2011055).
    Introduction
    Factors influencing melasma development Genetic backgrounds, exposure to UV, and female sex hormones are implicated as the main causes of melasma. Melanocytes undoubtedly play a critical role in melasma development and/or aggravation. However, increasing lines of evidence suggest that paracrine factors from neighboring keratinocytes or fibroblasts play a role in the pathogenesis of melasma.
    Conclusion Most of the published studies are performed in skin pigmentation not restricted to melasma. Although melasma is different from skin pigmentation induced by UV irradiation or inflammation, common mechanisms may be involved among these pigmentation disorders. Endogenous and exogenous factors affect melanogenesis in melasma via intracellular machinery, particularly cAMP, PKC, or both, as in other types of skin pigmentation. Currently, it is unclear which causative and triggering factor(s) would be more important and what possible scenarios exist in the case of multiple factor involvement in melasma development. Here, the role of genetic factor(s), UV irradiation, and female sex hormones in the pathogenesis of melasma was reviewed together with their role in other skin pigmentations. The important role of ion exchangers and miRNAs in melasma as well as other skin pigmentations was described. The factors associated with melasma development are summarized in Figure 2. The pathogenetic mechanisms of melasma could be heterogeneous in different individuals and ethnic groups. A personalized approach towards characterizing the pathogenesis may provide insights into solving the therapeutic difficulties associated with melasma.